TABLE 2

Kinetic parameters and DDI potential evaluation for CYP2J2-mediated metabolism of rivaroxaban or arachidonic acid (AA) in the presence of ibrutinib or osimertinib

DatasetSubstrate for EstimationKinetic ParameterR cut-off value
Ki,u (µM)Vmax(area ratio/min per pmol CYP2J2)KA (µM)KB (µM)Estimation MethodCalculated by Cu,max,ssCalculated by Cu,max,heart
Rivaroxaban-
osimertinib
Rivaroxaban4.94Competitive inhibition mode1.001
AA-osimertinibAA1.98Competitive inhibition mode1.0041.026
Rivaroxaban-
ibrutinib
Rivaroxaban0.0096254.2960.4481Two-site kinetic model1.050
AA-ibrutinibIbrutinib0.0515511.243.38Two-site kinetic model
AA34.3a5.51Two-site kinetic model1.0441.160
Ibrutinib0.0336499.130.9628Two-site kinetic model
  • Vmax, maximal metabolite formation velocity of respective substrate; KA and KB, equilibrium dissociation constants illustrated in Supplemental Fig. 1; Cu,max,ss, in vivo unbound peak plasma concentration; Cu,max,heart, in vivo unbound peak drug concentration in heart.

  • a Unstable parameter estimated by Prism 7.05.